CACNA1C p.Pro2000Ser
c.5998C>T · VCV3483948
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00133%, afr)
Conditions
1
Cardiovascular phenotype
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| REVEL | 0.02 | moderately benign-leaning |
|---|---|---|
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 0.17 | GERP -3.4 |
| Regional constraint | o/e 0.84 | unconstrained · MANE · 14 kb · p 2.9e-05 · regional, not allelic |
| Overall | ||
| CADD | 7.881 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00133%
African / African-American · 1/74,924 alleles
Overall
0.000124%
2/1,613,566 alleles · very rare
exomes 0/1,461,350 · genomes 2/152,216 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.00133% | 74,924 |
| South Asian | 0.0011% | 91,082 |
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- CACNA1C
- Protein
- p.Pro2000Ser
- Coding
- c.5998C>T
- MANE Select
- NM_000719
- Type
- single nucleotide variant
- Location
- chr12:2688660 (GRCh38)
- Gene constraint
- LOEUF 0.186 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
- Structure
- AlphaFold pLDDT 62.73 · 33 PDB
- Residue 2000
- a UniProt-annotated variant site (in nedhlss)
Similar variants
- CACNA1C p.Pro2000= Likely benign ★★ same residue
- CACNA1C p.Arg858His Pathogenic/Likely pathogenic ★★ same condition
- CACNA1C p.Arg860Gly Likely pathogenic ★★ same condition
- CACNA1C p.Asn537Asp Likely pathogenic ★★ same condition
- CACNA1C c.1113+4C>T Uncertain significance ★★ same condition
- CACNA1C c.2664-3C>T Uncertain significance ★★ same condition
- CACNA1C c.2794-3C>T Uncertain significance ★★ same condition
- CACNA1C c.3717+4A>G Uncertain significance ★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cacna1c-p-pro2000ser (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown